Campla Christie, Hoppe George, Yu Minzhong, Woda Juliana, Peachey Neal S, Josyula Vara Prasad, Stauffer Shaun R, Sears Jonathan E
Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44195, United States.
Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, United States.
J Med Chem. 2025 Jun 26;68(12):12392-12401. doi: 10.1021/acs.jmedchem.4c02186. Epub 2025 Jun 4.
Retinopathy of prematurity (ROP) blinds severely premature infants and is caused by oxygen supplementation. Hypoxia-inducible factor (HIF) stabilization during hyperoxia can prevent oxygen-induced retinopathy (OIR), the experimental correlate of ROP. Stabilization of hepatic HIF-1 alone can prevent OIR while contemporaneously protecting other organ systems, such as the lung and brain, from oxygen toxicity. However, HIF stabilization in central nervous system (CNS) oligodendrocytes reduces myelination. Here, we report the synthesis of small molecules specifically designed to not cross the blood-brain barrier based on a prodrug structure susceptible to hepatic carboxylesterases that release active drug. Twenty compounds were synthesized and rank ordered by Western blot, hypoxia response element binding, and reporter gene analysis. The lead compound prevented OIR, maintained normal CNS myelination, preserved the electroretinogram b-wave, and protected astrocytes. Strategies such as this might be broadly applicable to target specific hepatic functions while limiting off-target effects in other organs.
早产儿视网膜病变（ROP）会导致严重早产婴儿失明，其病因是吸氧。高氧期间缺氧诱导因子（HIF）的稳定可预防氧诱导性视网膜病变（OIR），这是ROP的实验对应物。仅肝脏HIF-1的稳定就能预防OIR，同时保护其他器官系统，如肺和脑免受氧毒性影响。然而，中枢神经系统（CNS）少突胶质细胞中HIF的稳定会减少髓鞘形成。在此，我们报告基于易被肝脏羧酸酯酶作用而释放活性药物的前药结构，合成了专门设计为不穿过血脑屏障的小分子。合成了20种化合物，并通过蛋白质印迹、缺氧反应元件结合和报告基因分析进行排序。先导化合物可预防OIR，维持正常的CNS髓鞘形成，保留视网膜电图b波，并保护星形胶质细胞。这样的策略可能广泛适用于靶向特定肝脏功能，同时限制对其他器官的脱靶效应。
